Benznidazole Absorption, Metabolism and Excretion Study

A Phase I, Open-label, Study of the Absorption, Metabolism and Excretion, of [14C]-Benznidazole (BNZ) Following a Single Oral Dose in Healthy Male Subjects

This Phase I ADME study will be conducted to evaluate the pharmacokinetics of benznidazole.

Study Overview

• Status: Completed
• Conditions: Healthy Male Subjects
• Intervention / Treatment: Drug: [14C]-Benznidazole

Detailed Description

This will be a single-site, open-label, non-randomized, single oral dose absorption, metabolism and excretion study in healthy male subjects. Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to dosing on Day 1. Subjects will be admitted into the Clinical Research Unit (CRU) on Day -1. Subjects will be confined to the CRU until at least Day 11 (240 hours postdose), and will be discharged from the CRU on Day 11 if all the following discharge criteria are met: >90% mass balance recovery; OR plasma/blood radioactivity levels below the limit of quantitation for 2 consecutive collections; and <1% of the total radioactive dose recovered in combined excreta (urine and faeces) in 2 consecutive 24-hour periods. If these criteria are not met by Day 11, subjects will remain in the CRU until all discharge criteria are met up to a maximum of Day 15 to continue 24-hour blood, urine and faeces collections for the analysis of total radioactivity, unless otherwise agreed upon by the Sponsor and Investigator. If the discharge criteria are not met by Day 15, subjects may be asked to collect 24-hour excreta samples on up to 2 further occasions on a nonresidential basis to allow extrapolation of urinary and faecal excretion. If needed, the 2 additional 24-hour nonresidential collections will occur on Day 21 (±1 day) and Day 28 (±1 day). If on the second occasion the subject has still not met the desired criterion, then the subject will be discharged from the study, per Investigator and Sponsor decision. Pharmacokinetic samples and radioanalytical samples will be obtained through at least 240 hours postdose, and possibly up to 4 weeks postdose (radioanalytical samples only), in case of not meeting discharge criteria. Samples for metabolite profiling/identification will be obtained through 240 hours postdose.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS2 9LH
    • Covance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Males of any race, between 35 and 65 years of age, inclusive, at screening.
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive, at screening.
3. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is acceptable) at screening or check-in as assessed by the Investigator (or designee).
4. Will agree to use contraception as detailed in Section 7.6.
5. History of a minimum of 1 bowel movement per day.
6. Able to comprehend and willing to sign an Inform Consent Form and to abide by the study restrictions.

Exclusion Criteria:

1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee).
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee).
3. History of dermatological conditions within the 6 months prior to dosing, such as rash, pruritus, and dermatitis, as determined by the Investigator (or designee).
4. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed). Cholecystectomy is acceptable.
5. History of alcoholism or drug/chemical abuse within 2 years prior to check-in.

6. Alcohol consumption of >28 units per week for males. One unit of alcohol equals

   ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits.

7. Positive alcohol breath test or positive urine cotinine test result, or positive urine drug screen (confirmed by repeat) at screening or check-in.
8. Positive hepatitis panel and/or positive human immunodeficiency virus test (Appendix 3).
9. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to check-in.
10. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to check-in, unless deemed acceptable per Investigator (or designee) and Sponsor decision.
11. Use or intend to use any prescription medications/products within 14 days prior to check-in, unless deemed acceptable by the Investigator (or designee).
12. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to check-in, unless deemed acceptable by the Investigator (or designee).
13. Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check-in, unless deemed acceptable per Investigator (or designee) and Sponsor decision.
14. Use of tobacco- or nicotine-containing products within 3 months prior to check-in.
15. Receipt of blood products within 2 months prior to check-in.
16. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening.
17. Poor peripheral venous access.
18. Have previously completed or withdrawn from this study or any other study investigating BNZ, and have previously received the investigational product.
19. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to check-in.
20. Subjects who have participated in any clinical trial involving a radiolabelled investigational product within 12 months prior to check-in.
21. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: [14C]-Benznidazole; A single dose of 100 mg [14C]-BNZ, orally administered on Day 1 following an overnight fast.	Drug: [14C]-Benznidazole; A single dose level of 100 mg; 200 μCi (7.4 MBq); Other Names: BNZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of BNZ in plasma	maximum observed concentration (Cmax) in plasma	Days 1-29
Mass balance of [14C]-BNZ	Mass balance of [14C]-BNZ in urine and faeces	Days 1-29
Chemical structure of [14C]-BNZ metabolites	Characterization of the chemical structure and identification of metabolites of [14C]-BNZ in plasma, urine, and faeces	Days 1-29
tmax of BNZ in plasma	time to maximum concentration (tmax) in plasma	Days 1-29
AUC0-t of BNZ in plasma	area under the concentration-time curve (AUC) from hour zero to the last measurable concentration (AUC0-t) in plasma	Days 1-29
AUC0-∞ of BNZ in plasma	AUC from time zero to infinity (AUC0-∞) in plasma	Days 1-29
% AUC extrap of BNZ in plasma	percentage extrapolation (% AUCextrap) in plasma	Days 1-29
t1/2 of BNZ in plasma	apparent terminal elimination half-life (t1/2) in plasma	Days 1-29
CL/Fof BNZ in plasma	apparent oral clearance (CL/F) in plasma	Days 1-29
Vz/F of BNZ in plasma	volume of distribution during the elimination phase for BNZ (Vz/F) in plasma	Days 1-29
Cmax of [14C]-BNZ in plasma	maximum observed concentration (Cmax) in plasma	Days 1-29
tmax of [14C]-BNZ in plasma	time to maximum concentration (tmax) in plasma	Days 1-29
AUC0-t of [14C]-BNZ in plasma	area under the concentration-time curve (AUC) from hour zero to the last measurable concentration (AUC0-t) in plasma	Days 1-29
AUC0-∞ of [14C]-BNZ in plasma	AUC from time zero to infinity (AUC0-∞) in plasma	Days 1-29
% AUC extrap of [14C]-BNZ in plasma	percentage extrapolation (% AUCextrap) in plasma	Days 1-29
t1/2 of [14C]-BNZ in plasma	apparent terminal elimination half-life (t1/2) in plasma	Days 1-29
Cmax of [14C]-BNZ in whole blood	maximum observed concentration (Cmax) in whole blood	Days 1-29
tmax of [14C]-BNZ in whole blood	time to maximum concentration (tmax) in whole blood	Days 1-29
AUC0-t of [14C]-BNZ in whole blood	area under the concentration-time curve (AUC) from hour zero to the last measurable concentration (AUC0-t) in whole blood	Days 1-29
AUC0-∞ of [14C]-BNZ in whole blood	AUC from time zero to infinity (AUC0-∞) in whole blood	Days 1-29
% AUCextrap of [14C]-BNZ in whole blood	percentage extrapolation (% AUCextrap) in whole blood	Days 1-29
t1/2 of [14C]-BNZ in whole blood	apparent terminal elimination half-life (t1/2) in whole blood	Days 1-29
Total radioactivity AUC ratio	Total radioactivity AUC ratio (blood/plasma)	Days 1-29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence and severity of Adverse Events (AEs)	The incidence of AEs will be presented by severity and by association with the study drug as determined by the Investigator (or designee).	Days 1-29
The incidence of laboratory abnormalities (haematology)	The incidence of laboratory abnormalities will be measured based on haematology test result.	Days 1-29
The incidence of laboratory abnormalities (clinical chemistry)	The incidence of laboratory abnormalities will be measured based on clinical chemistry test result.	Days 1-29
The incidence of laboratory abnormalities (urinalysis)	The incidence of laboratory abnormalities will be measured based on urinalysis test result.	Days 1-29
Measurement of QT interval (QTcB)	Measure of 12-lead electrocardiogram (ECG); QT interval calculated using the Bazett correction (QTcB) in millisecond	Days 1-29
Measurement of QT interval (QTcF)	Measure of 12-lead electrocardiogram (ECG); QT interval calculated using the Fridericia correction (QTcF) in millisecond	Days 1-29
Measurement of PR intervals	Measure of 12-lead electrocardiogram (ECG); PR intervals in millisecond.	Days 1-29
Measurement of QT intervals	Measure of 12-lead electrocardiogram (ECG); QT intervals in millisecond	Days 1-29
Measurement of QRS duration	Measure of 12-lead electrocardiogram (ECG); QRS duration in millisecond	Days 1-29
Measurement of RR	Measure of 12-lead electrocardiogram (ECG); RR in millisecond	Days 1-29
Measurement of heart rate	Measure of 12-lead electrocardiogram (ECG); heart rate in beats per minute (BPM)	Days 1-29
Measurement of blood pressure	Measure of supine systolic and diastolic blood pressure ( both in mmHg)	Days 1-29
Measurement of Physical Examination	Weight (in kilograms) and Height (in centimeters) will be measured	Days 1-29
Measurement of supine pulse rate	supine pulse rate (in beats/minute)	Days 1-29
Measurement body temperature	oral body temperature (in Degree Celsius)	Days 1-29
Measurement of Weight	weight (in kilograms)	Days 1-29
Measurement of Height	height (in centimeters) w	Days 1-29

Collaborators and Investigators

• Sponsor: Exeltis France
• Collaborators: Insud Pharma

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2018
• Primary Completion (Actual): September 2, 2018
• Study Completion (Actual): September 2, 2018

Study Registration Dates

• First Submitted: July 6, 2018
• First Submitted That Met QC Criteria: November 8, 2018
• First Posted (Actual): November 14, 2018

Study Record Updates

• Last Update Posted (Actual): November 14, 2018
• Last Update Submitted That Met QC Criteria: November 8, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Antiprotozoal Agents; Antiparasitic Agents; Trypanocidal Agents; Benzonidazole
• Other Study ID Numbers: LPRI747-103

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No